Unmodified polysaccharides can have undesirable biological properties, such as rapid clearance from circulation, rapid degradation, and/or allergenicity. Two polysaccharides that are commonly employed in pharmaceutical compositions and therapeutic methods include starch and dextran.
Starch is a naturally occurring, highly biocompatible polymer. When starch is introduced into the bloodstream it is rapidly digested by amylase. The fragments of the digested product are rapidly cleared from the vascular compartment through glomerular filtration and/or metabolism. For this reason hydroxyethyl starch (rather than starch) has been used as a long lasting plasma volume expander for several clinical indications. The hydroxyethylation of the starch molecule serves to slow the rate of digestion/excretion of the polymer.
Hydroxyethylation of starch using ethylene oxide or 2-chloroethanol has been common practice for production of colloidal plasma volume expanders. These processes have numerous disadvantages including employing highly toxic ethylene oxide, difficulty in controlling the extent of hydroxyethylation, inability to select among starch hydroxyl groups, toxic by products, and high cost. For example, hydroxyethylation with ethylene oxide occurs at any hydroxylic site, including sites that have already been hydroxyethylated, and with solvent, residual water, and impurities or side products in the reaction mixture. Lack of selectivity among sites on the starch molecule requires extensive hydroxyethylation of the starch, although modification of certain specific sites offers a greater degree of protection from enzymatic degradation.
Dextran has been used for a variety of pharmaceutical and therapeutic preparations over the past 40-50 years. The wide use of dextrans has included purified native dextrans for plasma replacement/volume expansion, dextran-active conjugates, iron-dextran iron supplements, and dextran coated particles for MRI contrast agents. For the most part dextran in a highly purified form is well tolerated by most of the patient population. However severe anaphylactoid responses are known to occur, and are in some cases severe enough to result in death.
These undesirable properties of polysaccharides employed in pharmaceutical compositions and therapeutic methods indicates the need for modified polysaccharides, such as modified starches and modified dextrans, that have more desirable biological properties than the native or unmodified polysaccharides.
The present invention relates to modified polysaccharides that have more desirable biological properties than the native or unmodified polysaccharides, pharmaceutical compositions including these modified polysaccharides, methods employing these modified polysaccharides, and methods of reducing the undesirable biological properties of these modified polysaccharides. Preferably, the modified polysaccharide is an oxidized and reduced polysaccharide. Preferably the polysaccharide is reduced with periodate. In a pharmaceutical composition the oxidized and reduced polysaccharide can be formulated in a pharmaceutically acceptable vehicle.
Preferred polysaccharides for modification according to the present invention include starch and/or dextran. An oxidized and reduced starch preferably exhibits a longer vascular half-life than unmodified starch, slower degradation by amylase than unmodified starch, and/or slower clearance from an animal than unmodified starch. An oxidized and reduced soluble dextran preferably exhibits reduced allergenicity compared to dextran. Preferably, the greater the extent of oxidation of the polysaccharide, the greater the vascular half-life, the slower the degradation, the slower the clearance, and/or the smaller the allergenicity.
The modified polysaccharide can be a component of or be employed to form a conjugate, such as a conjugate with a chelator. A preferred chelator is deferoxarnine (DFO).
A method of the invention includes increasing the vascular half life of starch by oxidizing and reducing the starch, and administering the oxidized and reduced starch into the circulation of a mammal. In another embodiment, the method of the invention includes decreasing the allergenicity of dextran by oxidizing and reducing the dextran, and administering the oxidized and reduced dextran into the circulation of a mammal. The dextran or starch administered can include a conjugate of the dextran or starch.